Adjuvants are agents added to, or used in conjunction with, vaccine antigens to augment or potentiate the specific immune response to the antigen. Their use in vaccines (especially with subunit vaccines) is crucial to vaccine efficacy, dose sparing, and rapid and durable immune protection against pathogens. However, only a limited number of adjuvants are currently used as vaccine components in the United States. New vaccine development is bottlenecked by the lack of safe and effective adjuvants. Discovery and development of novel adjuvants has emerged as a critical frontline effort in vaccine research. Saponin vaccine adjuvants, especially QS-21, isolated from the Quillaja Saponaria (QS) Molina tree bark extract, show promising adjuvant activity. QS-21 is one of the most sought after human vaccine adjuvants and has been used in over 100 clinical trials of vaccines against cancers and various infectious diseases. It is also a key component in the combination adjuvants currently being tested in over 20 clinical trials by the pharmaceutical industry. However, QS natural products have inherent drawbacks such as chemical instability, limited supply, difficult and low-yielding purification, and dose-limiting toxicity, which are the hurdles o their wider clinical use. There remains an imperative need of structurally-defined new QS saponin-based adjuvants with enhanced adjuvant activity, reduced toxicity, simplified formulation, and improved chemical stability and synthetic accessibility. Our recent research results indicate that the underexplored QS-17 and QS-18, the other two characterized components of QS tree bark extract, are potential leads for new adjuvant development. Due to the structural complexity, de novo synthesis and immunological study of defined QS-17/18 analogs remains unexplored. In this application, we propose efficient synthesis of QS-17/18-based new adjuvants. The new glycosylation approach recently developed in the PI's laboratory will be utilized to improve the overall synthetic efficiency. This application is a necessary step toward our ultimate goal of developing structurally defined vaccine adjuvants for clinical use. Specific aim: To synthesize and evaluate QS-17/18-based vaccine adjuvants.